The overall goal of the proposed project is to explore the role of the brain histone epigenome in modulating the effect of life experiences on cognitive decline and dementia. In prior work, we found that while cognitive decline in old age often results from one or more of three common brain diseases, AD, cerebrovascular disease, and Lewy body disease, these conditions only account for about 20% of the variance of cognition in older persons. Thus, factors other than neuropathology must make important contributions to cognitive function in old age. Over the past decade, our group has identified a range of life experiences that affect an individual's adult cognition but are not involved in the development of known age-related neuropathologic processes. A burgeoning literature suggests that the brain uses epigenetic marks as a means of linking experiential factors to stable behavioral changes including long term memory storage. We propose to conduct 900 epigenome- wide histone acetylation and phosphorylation scans on brain tissue from participants in an Exploratory Cohort (Rush Memory and Aging Project;R01AG17917) and a Confirmatory Cohort (Religious Orders Study (P30AG10161). The results of these epigenome-wide scans will be used in a programmatic series of analyses to explore the relation of the histone epigenome to detailed cognitive function tests and dementia status performed annually for up to 18 years, and to a wide range of life experiences (e.g., socioeconomic status, cognitive activities, psychological distress). The convergence of findings from these analyses will point to potential histone modifications linking life experiences to cognitive decline and dementia. We also will take advantage of available genome-wide genotyping and DNA methylation data on these subjects to examine the interaction between genetic variation and epigenetic marks on cognition and life experiences. In addition, the proposal will examine the relation of epigenetic marks to quantitative measures of the pathologic burden of the three most common causes of cognitive decline and dementia in old age, and a substudy will examine histone methylation in addition to acetylation and phosphorylation in multiple brain regions. Finally, the data will be made available to the research community to enable the investigation of fundamental genomic-epigenomic relationships in different brain regions, and to be explored for associations with a wide range of other clinical and biologic phenotypes available in these cohorts. Together, this integrative proposal represents a timely, novel and powerful approach that will transform our understanding of epigenetic contributions to age-related loss of cognition and dementia in humans. We are not aware of any other studies of older men and women of comparable size, relevant life experiences, clinical data, and follow-up and autopsy rates, in which these analyses can be performed. Thus, the project is well positioned to greatly accelerate the pace of research on age-related cognitive decline and dementia that will lay the groundwork for a wide range of potential interventions that are truly distinct from approaches currently under investigation. PUBLIC HEALTH RELEVANCE: Cognitive decline and dementia represent a large and growing public health problem. The prevention of dementia provides the best long-term strategy to reduce the human and economic toll of disease. The identification of epigenetic marks that link experiential factors with cognitive decline and dementia could provide important clues for the treatment and prevention of a common and devastating problem of aging and thereby improve the health and well being of older person.